CN101050176A - Method for preparing 4 - bromine 2,6 - difluoro benzoic acid - Google Patents
Method for preparing 4 - bromine 2,6 - difluoro benzoic acid Download PDFInfo
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- CN101050176A CN101050176A CN 200710040525 CN200710040525A CN101050176A CN 101050176 A CN101050176 A CN 101050176A CN 200710040525 CN200710040525 CN 200710040525 CN 200710040525 A CN200710040525 A CN 200710040525A CN 101050176 A CN101050176 A CN 101050176A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 60
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 44
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 229910003002 lithium salt Inorganic materials 0.000 claims abstract description 19
- 159000000002 lithium salts Chemical class 0.000 claims abstract description 18
- JHLKSIOJYMGSMB-UHFFFAOYSA-N 1-bromo-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(Br)=C1 JHLKSIOJYMGSMB-UHFFFAOYSA-N 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- 125000001979 organolithium group Chemical group 0.000 claims description 35
- 239000002904 solvent Substances 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
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- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 13
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 8
- 235000011089 carbon dioxide Nutrition 0.000 claims description 8
- IOJUPLGTWVMSFF-UHFFFAOYSA-N cyclobenzothiazole Natural products C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 8
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- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical group COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 6
- JCIVHYBIFRUGKO-UHFFFAOYSA-N lithium;2,2,6,6-tetramethylpiperidine Chemical group [Li].CC1(C)CCCC(C)(C)N1 JCIVHYBIFRUGKO-UHFFFAOYSA-N 0.000 claims description 6
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- 239000002994 raw material Substances 0.000 abstract description 6
- IRHPJGPQWZEZRX-UHFFFAOYSA-N 4-bromo-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=C(Br)C=C1F IRHPJGPQWZEZRX-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
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- 239000012044 organic layer Substances 0.000 description 12
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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Abstract
This invention provides a method for preparing 4-bromo-2, 6-difluorobenzoic acid. The method comprises: reacting 3, 5-difluoro bromobenzene and organic lithium reagent in organic solvent to obtain 4-substituted lithium salt of 3, 5-difluoro bromobenzene, and hydrolyzing to obtain 4-bromo-2, 6-difluorobenzoic acid. The method has such advantages as abundant raw materials, simple process, easy post treatment, mild reaction conditions, little pollution, and high yield.
Description
Technical field
The present invention relates to the synthetic field of organic chemistry, relate to 4-bromo-2 particularly, the preparation method of 6-difluoro-benzoic acid.
Background technology
Aromatic fluorine compound is mainly used the intermediate of physiologically active compounds such as used as pesticides, medicine, has good thermostability and higher fat-soluble.For example, as weedicide, sterilant, antitumor drug, anti-senile dementia disease drug, functional dye or the like.Because the activity of fluorine own is very high, in reaction, be difficult to control, especially on certain location, introduce and divide period of the day from 11 p.m. to 1 a.m difficulty bigger, so the preparation of organic fluorocompound is still the research field of a very challenging property.
Compound 4-bromo-2 of the present invention, the 6-difluoro-benzoic acid is the increasingly extensive intermediate of a kind of purposes, is the intermediate of synthesizing compound of liquid crystal, pharmaceutical compound and the agricultural chemical compound used always.
The method of carboxyl introducing aromatic nucleus has several, and the most frequently used is
1) oxidation style: alkyl benzene side chain can be by the acidity of potassium permanganate or potassium bichromate or basic solution or the oxidation of rare nitric acid institute
2) Grignard reagent synthesis method: behind Grignard reagent and the carbonic acid gas adduction, acidified water solves carboxylic acid
3) hydrolysis of itrile group.
Weak point of above-mentioned each reaction is: oxidation style is confined on the side chain of aromatic nucleus alkyl to be arranged, and strong oxidizer such as potassium bichromate is very big to the pollution of environment, in case destroy, is difficult to recover; The intermediate instability that grignard reaction generates, easily destroyed, be difficult to obtain needed compound; The hydrolysis of itrile group can produce a series of by products, therefore all is difficult to industrialization.
Above-mentioned synthetic method is for 4-bromo-2, and the such group of the 6-difluoro-benzoic acid position specific molecule of arranging is all inapplicable.
Particularly,, during the 6-difluoro-benzoic acid, adopt 3 usually with the synthetic 4-bromo-2 of Grignard reagent method, 5-two fluoro-1, the 4-dibromobenzene is as starting raw material, and its step is as follows:
The weak point of above-mentioned Grignard reagent synthesis method is: if synthesize 4-bromo-2 with above-mentioned Grignard reagent synthesis method, the 6-difluoro-benzoic acid, two Br are arranged on phenyl ring, when finally synthesizing Grignard reagent, the synthetic possibility is all arranged on two Br groups, and probability is suitable, is difficult to synthetic the finished product, poor selectivity.
Therefore, this area presses for a kind of 4-bromo-2, the preparation method of 6-difluoro-benzoic acid, this method is reacted with the industrial raw material of easily buying, technology is simple, easily row, mild condition, environmental pollution are little in aftertreatment, can make 4-bromo-2 with higher yields, 6-difluoro-benzoic acid product, but industrialization simultaneously.
Summary of the invention
The objective of the invention is to obtain a kind of 4-bromo-2, the preparation method of 6-difluoro-benzoic acid, this method is reacted with the industrial raw material of easily buying, technology is simple, easily row, mild condition, environmental pollution are little in aftertreatment, can make 4-bromo-2 with higher yields, 6-difluoro-benzoic acid product, but industrialization simultaneously.
Another object of the present invention is to provide a kind of purposes of organolithium reagent of the present invention.
One aspect of the present invention provides a kind of 4-bromo-2, the preparation method of 6-difluoro-benzoic acid, and it comprises the steps:
(a) 3,5-difluoro bromobenzene and organolithium reagent react in the presence of organic solvent, obtain 3, and the 4-position of 5-difluoro bromobenzene replaces lithium salts;
(b) step (a) obtain 3, the 4-position of 5-difluoro bromobenzene replaces lithium salts and obtains 4-bromo-2 through hydrolysis reaction, the 6-difluoro-benzoic acid.
In a preferred embodiment of the present invention, organic solvent is selected from pure ether solvent, ether solvent or its combination in the described step (a).
In a preferred embodiment of the present invention, described pure ether solvent is selected from diethylene glycol dimethyl ether, glycol dimethyl ether or its combination, and described ether solvent is selected from methyl tertiary butyl ether, ether, tetrahydrofuran (THF) or its combination.
In a preferred embodiment of the present invention, organic solvent and 3 described in the described step (a), the mol ratio of 5-difluoro bromobenzene is 4: 1～15: 1; And/or the temperature of reaction in the described step (a) is-100～50 ℃ a temperature range; And/or in the described step (a) 3, the mol ratio of 5-difluoro bromobenzene and organolithium reagent is 1: 0.5～1: 2.5.
Preferably, 3, the molar ratio of 5-difluoro bromobenzene and organolithium reagent is 1: 1～1: 1.05.
In a preferred embodiment of the present invention, the organolithium reagent described in the described step (a) is organic weak base lithium or sterically hindered amines lithium reagent.
In a preferred embodiment of the present invention, described sterically hindered amines lithium reagent is selected from 2,2,6,6-tetramethyl piperidine lithium, N-Lithiodiisopropylamide, Tetramethyl Ethylene Diamine lithium, 2-thiohydroxy benzothiazole lithium or its combination.
In a preferred embodiment of the present invention, space bulky amine lithium reagent is obtained by corresponding sterically hindered amines and lithium reagent reaction respectively in the described step (a), also be 2,2,6,6-tetramethyl piperidine, Diisopropylamine, Tetramethyl Ethylene Diamine, 2-thiohydroxy benzothiazole and lithium reagent reaction obtain.
Preferably, described lithium reagent is selected from metallic lithium, lithium alkylide or its combination.
Preferably, the alkyl in the described lithium alkylide is selected from normal-butyl, isobutyl-, n-propyl, sec.-propyl etc.
Preferably, synthesizing under organic solvent of organolithium reagent carries out.
Preferably, synthesizing in-90～30 ℃ of temperature ranges of organolithium reagent carries out.
In a preferred embodiment of the present invention, described step (b) is carried out in the presence of organic solvent, and described organic solvent is for being selected from diethylene glycol dimethyl ether, glycol dimethyl ether, methyl tertiary butyl ether, ether, tetrahydrofuran (THF) or its combination; And/or temperature of reaction described in the described step (b) is-80～30 ℃ a temperature range.
Preferably, described organic solvent is a tetrahydrofuran (THF).
In a preferred embodiment of the present invention, hydrolysis reaction described in the described step (b) comprise the steps: that step (a) obtains 3, feed carbonic acid gas in the 4-position replacement lithium salts of 5-difluoro bromobenzene, described carbonic acid gas and described 3, the mol ratio that the 4-position of 5-difluoro bromobenzene replaces lithium salts is 0-5: 1～5: 1.
Preferably, described molar ratio is 1-5: 1～2: 1.
In another aspect of the present invention, a kind of purposes of organolithium reagent is provided, it is used for from 3, the 5-difluoro bromobenzene sets out and prepares 4-bromo-2, the 6-difluoro-benzoic acid, described organolithium reagent comprises 2,2,6,6-tetramethyl piperidine lithium, N-Lithiodiisopropylamide, Tetramethyl Ethylene Diamine lithium, 2-thiohydroxy benzothiazole lithium or its combination.
Description of drawings
Fig. 1 is a 4-bromo-2, the 1H-NMR spectrogram of 6-difluoro-benzoic acid; X-coordinate is chemical shift δ ppm.
1H-NMR(CDCl
3，500MHz)δppm：12.76(m，1H，-OH)7.35(m，1H，-H)7.35(m，1H，-H)。
Embodiment
The inventor, is surprised to find that by improving preparation technology through extensive and deep research, adopts 3, and the 5-difluoro bromobenzene also can obtain selectivity preferably 3 as starting raw material, and the 4-position of 5-difluoro bromobenzene replaces lithium salts.In preferred implementation of the present invention, adopt specified conditions to make to adopt organolithium reagent to generate 4 to replace intermediates stable, and be difficult for destroyed, highly selective and obtain 3 with high yield, the 4-position replacement lithium salts of 5-difluoro bromobenzene.Finished the present invention on this basis.
In an embodiment of the invention, 4-bromo-2, the preparation method of 6-difluoro-benzoic acid, realize by following synthetic route:
As used herein, described " organic solvent " except as otherwise noted, refers to, help the reactant that the present invention relates to and product to disperse and not with the inert compound of its react with.Preferably, adopt aprotic polar solvent, for example pure particularly ether solvent, ether solvent or its combination.
As used herein, described " pure ether solvent " except as otherwise noted, refers to, the compound that the hydroxyl hydrogen atom on the condenses of dibasic alcohol or polyvalent alcohol is replaced by alkyl, and described compound and the reactant that the present invention relates to and product react with not.Particularly, for example, carbonatoms is the compound that one or both the hydrogen atom of hydroxyl in 2～4 times of bodies of 2～4 dibasic alcohol is replaced by the alkyl of carbonatoms 1～6.
As used herein, described " ether solvent " except as otherwise noted, refers to, and carbonatoms is 4～20 alkyl oxide or cycloalkyl ethers, and described compound and the reactant that the present invention relates to and product react with not.Described alkyl oxide or the alkyl or cycloalkyl of cycloalkyl ethers can be substituted.
As used herein, described " hydrolysis reaction " except as otherwise noted, refers to from 3, and the 4-position of 5-difluoro bromobenzene replaces lithium salts and forms 4-bromo-2, the reaction of 6-difluoro-benzoic acid.Particularly for example, feed carbonic acid gas or add other suitable reagent and make 3, the 4-position of 5-difluoro bromobenzene replaces the lithium salts hydrolysis and obtains 4-bromo-2, the 6-difluoro-benzoic acid.
As used herein, described " lithium reagent " except as otherwise noted, comprises metallic lithium, organolithium reagent.
As used herein, described " organolithium reagent " except as otherwise noted, is meant the lithium organometallic compound.For example, comprise alkylamine lithium, Cycloalkyl amine lithium, Heterocyclylalkyl amine lithium, arylamines lithium, aromatic heterocyclic amine lithium salts.Preferably, described organolithium reagent is selected from 2,2,6,6-tetramethyl piperidine lithium, N-Lithiodiisopropylamide, Tetramethyl Ethylene Diamine lithium, 2-thiohydroxy benzothiazole lithium or its combination.
As used herein, described " sterically hindered amines " except as otherwise noted, is meant a kind of organic amine compound, and nitrogen-atoms amino in its molecule connects carbochain (especially non-linear carbochain is as a tertiary butyl) group that amino is had space steric effect.Described " organic amine compound " comprises alkylamine (preferred a plurality of alkyl), Cycloalkyl amine, Heterocyclylalkyl amine, arylamines, aromatic heterocyclic amine.
As used herein, described " sterically hindered amines lithium reagent " except as otherwise noted, is meant the lithium metal compounds of sterically hindered amines.For example sterically hindered amines and lithium reagent react the organometallic compound that obtains.
As used herein, described " alkyl " except as otherwise noted, refers to the straight or branched alkane that contains 2-12 carbon atom.The alkane that preferably contains 4-8 carbon atom, for example, alkyl includes but not limited to ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.Described alkyl can be the alkyl of replacement or non-replacement.Substituting group on the alkyl comprises one or more amino, hydroxyl, thiohydroxy or its combination.
As used herein, described " cycloalkyl " except as otherwise noted, refers to the undersaturated cyclic hydrocarbon of saturated or part that contains 3-12 carbon atom.For example, " cycloalkyl " includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl, ring octyl group.
As used herein, described " Heterocyclylalkyl " refers to and contains 2-12 carbon atom and contain N at least, O, heteroatomic saturated or undersaturated cyclic hydrocarbon of part among the S.
As used herein, described " aryl " except as otherwise noted, refers to the mononuclear aromatics that contains 6 carbon atoms, the double ring arene of 10 carbon atoms, and the thrcylic aromatic hydrocarbon of 14 carbon atoms, and on each ring 1-4 substituting group can be arranged.For example, aryl includes but not limited to phenyl, naphthyl, anthryl.
As used herein, described " fragrant heterocycle " refers to the mononuclear aromatics of 5-8 atom, the double ring arene of 8-12 atom, the thrcylic aromatic hydrocarbon of 11-14 atom, and contain one or more heteroatomss (N for example, O, S)." fragrant heterocycle " includes but not limited to pyridyl, furyl, imidazolyl, benzimidazolyl-, pyrimidyl, thienyl, quinolyl, indyl, thiazolyl, benzothiazole.Described fragrant heterocycle can be the fragrant heterocycle of replacement or non-replacement.Substituting group on the virtue heterocycle comprises one or more amino, hydroxyl, thiohydroxy or its combination.
Compound provided by the present invention can be synthetic by marketable material and traditional chemical transform mode.
Above-mentioned synthetic method is the synthetic route of part of compounds of the present invention, according to above-mentioned example, those skilled in the art can synthesize other compounds of the present invention by adjusting diverse ways, and perhaps, those skilled in the art can synthesize compound of the present invention according to existing known technology.The synthetic compound can further be further purified by modes such as column chromatography, high performance liquid chromatography or crystallizations.
Synthetic chemistry is transformed, protection functional group methodology (protect or go and protect) is helpful to synthetic application compound, and be technology commonly known in the art, as R.Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, JohnWiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis has open among the John Wiley and Sons (1995).
Other aspects of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Unless otherwise defined or explanation, same meanings of being familiar with of all specialties used herein and scientific words and those skilled in the art.Any in addition method similar or impartial to described content and material all can be applicable in the inventive method.
Below preparation method of the present invention is described in detail:
4-bromo-2,6-difluoro-benzoic acid preparation method's step
4-bromo-2 of the present invention, the preparation method of 6-difluoro-benzoic acid, it comprises the steps:
(a) 3,5-difluoro bromobenzene and organolithium reagent react in the presence of organic solvent, obtain 3, and the 4-position of 5-difluoro bromobenzene replaces lithium salts;
(b) step (a) obtain 3, the 4-position of 5-difluoro bromobenzene replaces lithium salts and obtains 4-bromo-2 through hydrolysis reaction, the 6-difluoro-benzoic acid.
In a preferred embodiment of the present invention, 4-bromo-2 of the present invention, the preparation method of 6-difluoro-benzoic acid comprises the steps:
(a) 3,5-difluoro bromobenzene and organolithium reagent react in the presence of organic solvent, and it is good 3 to obtain regioselectivity, and the 4-position of 5-difluoro bromobenzene replaces lithium salts;
(b) to replace lithium salts logical carbonic acid gas in the presence of organic solvent extremely saturated the 4-position that obtains of step (a), obtains 4-bromo-2 through hydrolysis reaction, the 6-difluoro-benzoic acid.
Synthetic 4-bromo-2 during the 6-difluoro-benzoic acid, adopts 3 usually in this area, 5-two fluoro-1, and the 4-dibromobenzene is as initial product.And the present invention adopts 3, the 5-difluoro bromobenzene, and it can be synthetic by marketable material and traditional chemical transform mode.
The substitution reaction of step (a)
Organic solvent in the substitution reaction preferably is selected from pure ether solvent, ether solvent or its combination.
Preferably, described pure ether solvent is formula (I) compound:
RO(CxH2xO)nR’(I)
Described R and R ' are identical or different separately C1～C10 alkyl or H key, and R and R ' can not be H simultaneously; Preferably, described R and R ' are alkyl; More preferably, described alkyl is a methyl;
Described x is 2～4 positive integer; Preferably x is 2;
Described n is 2～4 positive integer.
Most preferably, pure ether solvent of the present invention is selected from diethylene glycol dimethyl ether (R and R ' are methyl, and x is 2, and n is 2), glycol dimethyl ether (R and R ' are methyl, and x is 2, and n is 1) or its combination.
Ethers reagent of the present invention is preferably ether, methyl tertiary butyl ether, ether, tetrahydrofuran (THF) or its combination.
In the substitution reaction of the present invention, the consumption of organic solvent is preferably: organic solvent and 3 described in the described step (a), the mol ratio of 5-difluoro bromobenzene are 4: 1～10: 1.
In the substitution reaction of the present invention, organolithium reagent preferably can be so that the middle stable reagent of lithium compound that generates.Particularly for example, organolithium reagent is the organic weak base lithium or has sterically hindered organolithium reagent, preferable space bulky amine lithium reagent.The lithium compound (also being the lithium compound intermediate) that generates in the middle of described sterically hindered size makes is stable to get final product.Preferably, sterically hindered amines is secondary amine or tertiary amine compound, comprises alkylamine (preferably two or more alkyl replace), Cycloalkyl amine, Heterocyclylalkyl amine, arylamines, aromatic heterocyclic amine.The example of alkylamine such as Diisopropylamine, Tetramethyl Ethylene Diamine etc.; The example of Cycloalkyl amine is as 2,2,6, and the example such as the benzothiazole or derivatives thereof of 6-tetramethyl piperidine and its derivative (for example 1 and 4 by the replacement of groups such as alkyl), aromatic heterocyclic amine are as 2 benzothiazoles that replaced by thiohydroxy.
Preferably, the organolithium reagent described in the described step of the present invention (a) is selected from 2,2,6,6-tetramethyl piperidine lithium, N-Lithiodiisopropylamide, Tetramethyl Ethylene Diamine lithium, 2-thiohydroxy benzothiazole lithium or its combination.
Usually, from 3, the 5-difluoro bromobenzene preparation 4-bromo-2 that sets out, in the 6-difluoro-benzoic acid, since 3, three hydrogen are arranged on the 5-difluoro bromobenzene, so organolithium reagent and 3, the intermediate that the 5-difluoro bromobenzene forms can have multiple, comprise 2,4,6, and in a preferred embodiment of the present invention, the above-mentioned sterically hindered lithium reagent that has living space makes particularly 4 selectivity that replace intermediate improve greatly, and keep it stable, thereby improved the efficient of this operational path greatly up to hydrolysis.
More preferably, have sterically hindered organolithium reagent and be selected from 2,2,6 when described, when 6-tetramethyl piperidine lithium, N-Lithiodiisopropylamide, Tetramethyl Ethylene Diamine lithium, 2-thiohydroxy benzothiazole lithium or its combination, 4 selectivity that replace intermediates reach more than 99%.
More preferably, organolithium reagent is respectively by 2,2,6 in the described step (a), and 6-tetramethyl piperidine, Diisopropylamine, Tetramethyl Ethylene Diamine, 2-thiohydroxy benzothiazole and lithium reagent reaction obtain;
Wherein said lithium reagent is selected from metallic lithium, lithium alkylide or its combination.
Preferably, the alkyl in the described lithium alkylide is selected from straight chained alkyl.The C1 of straight or branched～C8 alkyl for example.
The synthesis temperature of organolithium reagent is not particularly limited, only otherwise goal of the invention of the present invention is produced restriction to get final product.Particularly for example, synthesizing under temperature of reaction-80～30 ℃ of above-mentioned organolithium reagent carries out.Those skilled in the art are appreciated that also above-mentioned temperature of reaction also is feasible under the identical temperature of substitution reaction.
Preferably, synthesizing under organic solvent of above-mentioned organolithium reagent carries out.Certainly, those skilled in the art are appreciated that also above-mentioned organolithium reagent also can directly react with lithium reagent and do not need specially to add solvent in reaction system; Those skilled in the art are appreciated that also above-mentioned organolithium reagent can separate in addition, also can not separate and directly carry out the reaction of subsequent step.
In the substitution reaction of the present invention, temperature of reaction is not particularly limited, only otherwise goal of the invention of the present invention is produced restriction to get final product.Temperature of reaction in the described step (a) is-100～50 ℃ a temperature range.Preferably ,-90～30 carry out in ℃ temperature range.
In the substitution reaction of the present invention, the ratio of reactant and organolithium reagent is not particularly limited, only otherwise goal of the invention of the present invention is produced restriction to get final product.Particularly for example 3, the mol ratio of 5-difluoro bromobenzene and organolithium reagent is 1: 0.5～1: 2.5.Preferably, described ratio is 1: 1～1: 1.05.
The hydrolysis reaction of step (b)
Hydrolysis reaction of the present invention is not particularly limited, and can adopt method commonly used in this area to carry out, as long as obtain corresponding carboxylic acid cpd from organolithium reagent.
In the hydrolysis reaction of the present invention, the ratio of hydrolysing agent and intermediate is not particularly limited, only otherwise goal of the invention of the present invention is produced restriction to get final product.The mol ratio of carbonic acid gas and lithium salts is 0.5: 1～5: 1 described in for example described particularly step (b).Preferably, described molar ratio is 1.5: 1～2: 1.
In the hydrolysis reaction of the present invention, organic solvent is not particularly limited, only otherwise goal of the invention of the present invention is produced restriction to get final product.Particularly for example organic solvent described in the step (b) for being selected from diethylene glycol dimethyl ether, glycol dimethyl ether, methyl tertiary butyl ether, ether, tetrahydrofuran (THF) or its combination.Preferably, described solvent is a tetrahydrofuran (THF).
In the hydrolysis reaction of the present invention, temperature of reaction is not particularly limited, only otherwise goal of the invention of the present invention is produced restriction to get final product.Temperature of reaction described in for example described particularly step (b) is-80～30 ℃ a temperature range.
The invention has the advantages that:
(1) preparation method of the present invention reacts with the industrial raw material of easily buying, and the technology of this method is simple, aftertreatment is easily gone, can be made 4-bromo-2 with higher yields, 6-difluoro-benzoic acid product, easily industrialization simultaneously.
(2) preparation method's mild condition of the present invention, environmental pollution is little.
Below in conjunction with specific embodiment, further illustrate the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example usually according to normal condition, for example is " condition in the smooth organic chemistry handbook of Bel Si (Chemical Industry Press, 1996), or the condition of advising according to manufacturer.Ratio and per-cent are based on weight, unless stated otherwise.
Embodiment 1:
In the 1L bottle, add 300ml THF (molecular weight 72.11, density 0.8892,3.7mol), 10% butyl lithium solution 0.39mol (250g) and 2,2,6,6-tetramethyl piperidine (0.39mol 56g), drip 3 down at-10 ℃, 5-difluoro bromobenzene (99.8%) 0.3mol (58g) (solvent and 3, the mol ratio of 5-difluoro bromobenzene are 12.3: 1), stir about 30min is cooled to-90 ℃ of logical CO
2Gas leads to saturated.CO
2Begin nature intensification degree after saturated.Temperature adds 400ml dilute hydrochloric acid for-10 ℃ the time in rising to, and to PH＜1, has told the upper strata organic layer, the water layer extracted with diethyl ether, and organic layer is through washing, drying, steaming desolventizes, and obtains product 71 and restrains, and product is a beige.Behind recrystallization, obtain 59 gram white products, HPLC content 99.4%, former molar yield=88.9% of expecting product.
Embodiment 2:
In the 1L bottle, add 400ml ether (molecular weight 74.12, density 0.7135,3.85mol), 10% butyl lithium solution 0.15mol (96g) and 0.15mol (18g) Tetramethyl Ethylene Diamine, drip 3 down at 50 ℃, 5-difluoro bromobenzene 0.3mol (58g) (solvent and 3, the mol ratio of 5-difluoro bromobenzene is 12.8: 1), stir about 30min is cooled to 10 ℃ of logical CO
2Gas leads to saturated.CO
2Begin nature intensification degree after saturated.Temperature adds 400ml dilute hydrochloric acid when being 30 ℃ in rising to, and to PH＜1, has told the upper strata organic layer, the water layer extracted with diethyl ether, and organic layer is through washing, drying, steaming desolventizes, and obtains product 58 and restrains, and product is a beige.Through recrystallization, obtain 49 gram white products, HPLC content 99.0%.Former molar yield=67.8% of expecting product
Embodiment 3:
In the 2L bottle, add 800ml methyl tertiary butyl ether (molecular weight 88.15, density 0.7404,6.72mol), 10% butyl lithium solution 0.75mol (480g) and Diisopropylamine 0.75mol (55g), stir about 30min drips 3 down at 10 ℃, 5-difluoro bromobenzene 0.75mol (145g) (solvent and 3, the mol ratio of 5-difluoro bromobenzene is 8.96: 1), be cooled to-30 ℃ of logical CO
2Gas leads to saturated.CO
2Begin nature intensification degree after saturated.Temperature adds 400ml dilute hydrochloric acid when being 0 ℃ in rising to, and to PH＜1, has told the upper strata organic layer, the water layer extracted with diethyl ether, and organic layer is through washing, drying, steaming desolventizes, and obtains product 158 and restrains, and product is a beige.Through recrystallization, obtain 141 gram white products, HPLC content 99.6%.Former molar yield=78.0% of expecting product.
In the 1L bottle, add 300ml THF (molecular weight 72.11, density 0.8892), 10% butyl lithium solution 0.39mol (250g) and 0.15mol (18g) Tetramethyl Ethylene Diamine, drip 3 down at-10 ℃, 5-difluoro bromobenzene (99.8%) 0.3mol (58g), stir about 30min is cooled to 0 ℃ of logical CO
2Gas leads to saturated.CO
2Begin nature intensification degree after saturated.Temperature adds 400ml dilute hydrochloric acid when being 5 ℃ in rising to, and to PH＜1, has told the upper strata organic layer, the water layer extracted with diethyl ether, and organic layer is through washing, drying, steaming desolventizes, and obtains product 50 and restrains, and product is a beige.Behind recrystallization, obtain 45 gram white products, HPLC content 99.2%, former molar yield=67.1% of expecting product.
Embodiment 5
In the 1L bottle, add 300ml THF (molecular weight 72.11, density 0.8892), Mg and consider 0.39mol (9.36g) to be worth doing, drip 3 down at-10 ℃, 5-difluoro bromobenzene (99.8%) 0.3mol (58g), stir about 30min is cooled to 0 ℃ of logical CO
2Gas leads to saturated.CO
2Begin nature intensification degree after saturated.Add 400ml dilute hydrochloric acid when temperature is 5 ℃ in rising to,, told the upper strata organic layer to PH＜1, the water layer extracted with diethyl ether, organic layer is through washing, and drying is distilled, and obtains product 16 grams, and product is a beige.Behind recrystallization, obtain 8 gram white products, HPLC content 99.1%, former molar yield=12% of expecting product.
Embodiment 6
In the 1L bottle, add the 400ml ether (molecular weight 74.12, density 0.7135 3.85mol), 10% butyl lithium solution 0.39mol (250g), drip 3 down at-10 ℃, 5-difluoro bromobenzene (99.8%) 0.3mol (58g), stir about 30min is cooled to-90 ℃ of logical CO
2Gas leads to saturated.CO
2Begin nature intensification degree after saturated.Add 400ml dilute hydrochloric acid when rising to interior temperature,, told the upper strata organic layer to PH＜1 for-10 ℃, the water layer extracted with diethyl ether, organic layer is through washing, and drying is distilled, and obtains product 46 grams, and product is a beige.Behind recrystallization, obtain 28 gram white products, HPLC content 99.0%, former molar yield=41% of expecting product.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. 4-bromo-2, the preparation method of 6-difluoro-benzoic acid is characterized in that, comprises the steps:
(a) 3,5-difluoro bromobenzene and organolithium reagent react in the presence of organic solvent, obtain 3, and the 4-position of 5-difluoro bromobenzene replaces lithium salts;
(b) step (a) obtain 3, the 4-position of 5-difluoro bromobenzene replaces lithium salts and obtains 4-bromo-2 through hydrolysis reaction, the 6-difluoro-benzoic acid.
2. the method for claim 1 is characterized in that, organic solvent is selected from pure ether solvent, ether solvent or its combination in the described step (a).
3. method as claimed in claim 1 or 2 is characterized in that, described pure ether solvent is selected from diethylene glycol dimethyl ether, glycol dimethyl ether or its combination, and described ether solvent is selected from methyl tertiary butyl ether, ether, tetrahydrofuran (THF) or its combination.
4. method as claimed in claim 1 or 2 is characterized in that,
Organic solvent and 3 described in the described step (a), the mol ratio of 5-difluoro bromobenzene are 4: 1～15: 1; And/or
Temperature of reaction in the described step (a) is-100～50 ℃ a temperature range; And/or
In the described step (a) 3, the mol ratio of 5-difluoro bromobenzene and organolithium reagent is 1: 0.5～1: 2.5.
5. method as claimed in claim 1 or 2 is characterized in that, the organolithium reagent described in the described step (a) is organic weak base lithium or sterically hindered amines lithium reagent.
6. method as claimed in claim 5 is characterized in that, described sterically hindered amines lithium reagent is selected from 2,2,6,6-tetramethyl piperidine lithium, N-Lithiodiisopropylamide, Tetramethyl Ethylene Diamine lithium, 2-thiohydroxy benzothiazole lithium or its combination.
7. method as claimed in claim 6, it is characterized in that, space bulky amine lithium reagent is obtained by corresponding sterically hindered amines and lithium reagent reaction respectively in the described step (a), also be 2,2,6,6-tetramethyl piperidine, Diisopropylamine, Tetramethyl Ethylene Diamine, 2-thiohydroxy benzothiazole and lithium reagent reaction obtain.
8. method as claimed in claim 1 or 2 is characterized in that,
Described step (b) is carried out in the presence of organic solvent, and described organic solvent is for being selected from diethylene glycol dimethyl ether, glycol dimethyl ether, methyl tertiary butyl ether, ether, tetrahydrofuran (THF) or its combination; And/or
Temperature of reaction described in the described step (b) is-80～30 ℃ a temperature range.
9. method as claimed in claim 1 or 2 is characterized in that, hydrolysis reaction comprises the steps: described in the described step (b)
Step (a) obtain 3, the 4-position of 5-difluoro bromobenzene replaces in the lithium salts and feeds carbonic acid gas, described carbonic acid gas is with described 3, the mol ratio of the 4-position replacement lithium salts of 5-difluoro bromobenzene is 0.5: 1～5: 1.
10. the purposes of an organolithium reagent is characterized in that, is used for from 3, the 5-difluoro bromobenzene sets out and prepares 4-bromo-2, the 6-difluoro-benzoic acid, and described organolithium reagent comprises 2,2,6,6-tetramethyl piperidine lithium, N-Lithiodiisopropylamide, Tetramethyl Ethylene Diamine lithium, 2-thiohydroxy benzothiazole lithium or its combination.
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